Biosketch

I am the first woman to receive a PhD degree from the Johns Hopkins School of Medicine. I received my first R01 award in 1970 and have since been continuously supported by NIH grants. I am the author of 310 publications in outstanding peer-reviewed journals and numerous review articles and book chapters and I am the inventor of 14 US and foreign patents. I trained over 60 postdoctoral and 37 predoctoral fellows, virtually all of whom hold Academic Positions.

Over the last 35-40 years my laboratory has made major significant contributions to science. One of these has been the development of a better understanding of the molecular and cellular factors that define infection with Herpes simplex virus type 2 (HSV-2) and the role that it plays in human disease. Another major contribution has been the elucidation of factors involved in disease development and the demonstration that inhibitory (Tregs and Th2) cell pathways are involved in the causation of recurrent disease. These efforts culminated in the development of a therapeutic HSV vaccine that has successfully completed phase I/II clinical studies. A third significant contribution has been the definition of viral genes in disease development. We showed that a HSV-2 gene regulates cell proliferation, unregulated cellular replication and neoplastic transformation, associated with human cancer and a viral gene is involved in the control of neuronal cell life/death decisions. We established the mechanism whereby this viral gene inhibits neuronal cell death and documented its evolutionary relationship to the cellular small heat shock protein H11 (HspB8), which we were the first to identify and clone and show that it has tumor suppressor activity. Another significant contribution to science made by our laboratory is in the understanding of recurrent erythematous skin lesions, known as erythema multiforme. We showed that these lesions are caused by non-permissive HSV infection of circulating CD34+ stem cells and the resulting induction of stem cell differentiation into antigen-presenting dendritic cells that target the skin.

The most recent significant contribution to science made by our laboratory is in oncolytic virotherapy, an emerging cancer therapeutic approach with relatively modest clinical efficacy. We developed an oncolytic virus (OV), known as DPK, with potent oncolytic activity in melanoma due to its multimodal activity. ∆PK lyses cancer stem cells (CSCs), activates numerous program cell death pathways and reverses the immunosuppressive tumor microenvironment responsible for therapeutic resistance. Specifically, ∆PK decreases tumor cell secretion of immunosuppressive and pro-cancerous cytokines (viz. IL-10 and IL-18) while concomitantly increasing secretion of pro-inflammatory cytokines (TNF-α, GM-CSF, IL-6 and IL-1β). It upregulates the NKG2D ligand, MICA expressed by cytotoxic NK and T cells, and downregulates the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen-4 (CTLA-4). The virus is well tolerated in human patients in whom it also alters the T cell balance in favor of immunostimulatory responses.

Research Interests

My current studies focus on the role of genetics in alcoholism. Alcohol-dependence is a complex disorder that initiates with episodes of excessive alcohol drinking known as binge drinking and has a 50-60% risk contribution from inherited susceptibility genes. Cognitive impulsivity is a heritable trait that may set the stage for transition to alcohol dependence but its role in the ethanol-seeking behavior and the involved genes are still poorly understood. We developed novel technologies designed to address these limitations, including the generation of non-replicating HSV-based siRNA vectors. We showed that the immunomodulatory gene Toll-like receptor 4 (TLR4) is over-expressed in neurons from binge-drinking alcohol-preferring P rats at brain sites that regulate both impulsivity and binge drinking. TLR4 is expressed by GABAergic or dopaminergic neurons at distinct brain sites. It is innately activated in the alcohol-preferring rats and regulates both impulsivity and the initiation of excessive alcohol drinking. Involved pathways include expression of the chemokine MCP-1, which also functions as a neurotransmitter that controls neuronal plasticity and excitability, and a cAMP-dependent protein kinase (PKA)/cyclic AMP response element binding protein (CREB) signal that regulates dopamine synthesis through tyrosine hydroxylase production. GABA, the GABAA receptor a2 subunit, the hormone corticotropin-releasing factor CRF and neuronally expressed IgG are involved in the regulation of the TLR4 signal. Ongoing studies are designed to further elucidate the mechanisms that regulate TLR4 activation as it relates to the initiation of excessive alcohol drinking and its transition to alcohol dependence. The mechanisms whereby innate immunity-related signaling control addiction through the regulation of plasticity and excitability are also under investigation.